Class III antiarrhythmic agents are recognized as having the ability to markedly prolong dog Purkinje fiber action potential duration without producing significant changes in maximal upstroke velocity. Unlike Class I antiarrhythmic agents, a pure Class III agent displays no effect on cardiac sodium channels. The electrophysiologic properties of a compound defining a Class III activity profile are observed in vivo as negligible effects on atrial, ventricular and H-V conduction times while producing a marked increase (greater than 20 percent) in both the atrial and ventricular refractory periods. In contrast, Class 1 agents demonstrate a marked slowing of ventricular conduction velocity, generally without significant changes in the refractory period. Recent reviews of these agents are: Bexton et al.; Pharmac. Ther. 1982, 17, 315-55; Vaughan-Williams, J. Clin. Pharmacol, 1984, 24, 129-47; Steinberg et al.; Ann. Rep. Med. Chem. 1986, 21, 95-108.
Oinuma et al. have disclosed 4'-[[1-[2-(6-methyl-2-pyridyl)ethyl]-4-piperidyl]carbonyl]methanesulfonami de (E-4031) and related piperidine derivatives as potential Class III antiarrhythmic agents in European Patent Application 0235752, Sep. 9, 1987, and further describe their pharmacology in J. Med. Chem, 1990, 33, 903. Closely related thio-substituted piperidines with similar activity are disclosed by Oinuma et al. in European Patent Application 0304888, Mar. 1, 1989.
Carr et al. have disclosed various 1,4-disubstituted piperidine derivatives possessing the acetamide moiety with similar Class III effects in European Patent Application 0320983, Jun. 21, 1989.
Lis et al. have disclosed derivatized alkanolamines possessing the piperazine moiety in WO 90/00548, Jan. 25, 1990 and further describe their Class III antiarrhythmic activity in J. Med. Chem. 1990, 33, 2883.